The introduction of combined glucocorticoid and immunosuppressive therapy transformed the survival of patients with systemic vasculitis. Although there has been little change in the actual agents used to treat AAV, there has been considerable progress in optimising treatment regimens to minimise toxicity [93
]. Despite these efforts, however, cyclophosphamide and high-dose glucocorticoids remain toxic and 10% of patients are intolerant of these therapies. In addition, relapsing disease is common, with over 50% of patients experiencing a relapse within 5 years despite continued immunosuppression. Furthermore, refractory disease affects 10 to 20% of patients and poses a significant management challenge. There is therefore a clear need for more efficacious and safer therapies.
Rituximab is the best studied biological agent in AAV. The recently published randomised controlled trials RITUXVAS and RAVE have shown that rituximab is similar to cyclophosphamide, in terms of both efficacy and safety, for induction of remission in AAV in the short term. Subgroup analysis in the RAVE trial found the efficacy of rituximab to be superior to at 6 months for patients with relapsing disease.
Potential adverse effects of any new therapy must be carefully evaluated prior to recommendation of use. Infection, particularly in the context of hypogamma-globulinaemia, is a concern following administration of rituximab. In a retrospective cohort of 105 patients with primary systemic vasculitis or SLE, 39% developed a mild infection, most commonly of the urinary tract, chest or upper respiratory tract. A total 28.5% of patients developed a severe infection, which is higher than in studies of rituximab in rheumatoid arthritis but lower than in vasculitis trials using alemtuzumab or deoxyspergualin. Patients with low IgG and IgM levels have been shown to be at significantly increased risk of infection, and immunoglobulin levels, as well as white cell counts, should be routinely monitored following rituximab administration [94
]. In a retrospective series, late-onset neutropaenia occurred in 3/13 patients with GPA, all of whom developed infection needing intravenous antibiotics [95
]. Further study is required into longer-term outcomes after rituximab treatment, including cardiovascular disease, infertility and malignancy.
Concern has been expressed regarding the development of progressive multifocal leucoencephalopathy, an opportunistic infection caused by the JC virus. At least 57 cases have been reported following rituximab therapy, four in patients with autoimmune disease (two SLE patients, one rheumatoid arthritis patient and one immune thrombocytopaenia patient) [96
]. This association is confounded by the use of immunosuppression prior to the administration of rituximab, and the observation that progressive multifocal leucoencephalopathy is seen in patients with autoimmune disease not treated with rituximab. Unfortunately, these reports highlight the possibility of rare, severe, adverse effects that may not be detected in clinical trials. It is important that patients who receive new biological agents enter registry follow-up, to document late outcomes and side effects. Relapses are common after rituximab, and maintenance strategies are required that keep patients well yet avoid complications of prolonged B-cell depletion.
Improved patient subgrouping and tailoring of therapy will reduce unnecessary exposure to toxic therapies. Older people pose particular challenges. The peak incidence of AAV occurs in the age group of 65 to 70 years. One-year mortality is 23% in those aged over 60 years, compared with just 5% in the under-60 age group. Much of the excess mortality is due to infection. More attention is being focused on older people. The CORTAGE study, coordinated by the French Vasculitis Study Group, is comparing low-dose glucocorticoids with standard-dose glucocorticoids, with standard immunosuppression in patients over 65 years old. Newer biomarkers are required to predict treatment response, relapse risk and drug selection. Urinary monocyte chemoattractant protein-1 correlates with the degree of active vasculitis on renal biopsy and may become useful in renal vasculitis [97
]. With advances in understanding of the genetic basis of disease and early results of transcriptome analysis, there is a real possibility that other clinically useful tests will become available.
Advances in classification and evidence-based therapy of vasculitis have resulted from collaborative networks both within and between countries. To date, there has been little pharmaceutical investment in these disorders. With increasing physician collaboration and industry interest in rare diseases, progress is likely to accelerate. Consensus recommendation statements have been published that will lead to harmonisation of therapy. With the establishment of registries and quality indicators there is hope that the variable quality of care that patients have received in the past will be improved.